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Catalyst-dependent Stereodivergent and Regioselective Synthesis of Indole-fused Heterocycles through Formal Cycloadditions of Indolyl-allenes Liang-Yong Mei, Yin Wei, Xiang-Ying Tang, and Min Shi J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2015 Downloaded from http://pubs.acs.org on June 6, 2015
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Catalyst-dependent Stereodivergent and Regioselective Synthesis of Indole-fused Heterocycles through Formal Cycloadditions of Indolyl-allenes Liang-Yong Mei,‡ Yin Wei,† Xiang-Ying Tang,†* Min Shi† ‡* †
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Lu, Shanghai 200032, China. ‡ Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Meilong Road No. 130, Shanghai 200237, China. Supporting Information ABSTRACT: Stereo- and regioselective construction of poly-heterocycles, especially those with several contiguous stereocenters, is still a challenge. In this paper, catalyst-dependent stereodivergent and regioselective synthesis of indole-fused heterocycles through formal cycloadditions of indolyl-allenes have been developed. The reaction features total reversion of an all-carbon quaternary stereocenter when gold or platinum complex was employed as the catalyst through [3+2] cycloaddition of allene with indole, affording different diazabenzo[a]cyclopenta[cd]azulenes as epimers, respectively. In addition, in the presence of IPrAuCl and AgNTf2, highly regioselective exo-type [2+2] cycloaddition was observed, in which allene served as a 2C synthon. This methodology provides a simple and straightforward approach for the construction of indole-fused tricyclic systems under mild conditions in an atom-economical way.
INTRODUCTION Indole fused poly-heterocycles, as constituents of diverse natural alkaloids and pharmaceutical agents, have drawn much attention of organic and bioorganic chemists during [1] the past several decades. In the realm on the development of synthetic methodology towards such compounds, intramolecular cycloaddition of allene as a 3C or 2C synthon with indole is a viable strategy to achieve this goal. Indeed, several elegant works have been done using allenes as three-carbon components in transition-metal-catalyzed [3+n] cycloaddi[2] tion. For instance, Gagosz and coworkers started the pioneering work by reporting a formal Au-catalyzed [3+2] intramolecular cyclization of enynyl acetates, which went [3] through allenyl ester intermediates. Zhang et al. showed a Pt-catalyzed [3+2] annulation of allenyl esters generated in [4] situ via a 3,3-rearrangement of propargyl precursors. Additionally, under varied reaction conditions, the alternative [2+2] and [4+2] cycloadditions could be selectively induced, in which the employed allenes reacted with other substances [5] through one of the two double bonds. Based on these elegant studies as well as our ongoing efforts in exploring novel [6] synthetic routes for indole-fused scaffolds, we envisaged that indolyl-allene substrates 1 could undergo a certain cy[7], [8] cloaddition under Au- or Pt catalysis. However, due to the multiple reactive sites of allenes, there are several significant challenges to realize the desired reaction with respect to chemo- and stereoselectivity. As for the
intramolecular [3+2] cycloaddition, to stereocontrol the allcarbon quaternary stereocenter is very difficult (Scheme 1, a). Moreover, it is also troublesome to regioselectively control the endo- or exo-type in [2+2] cycloaddition (Scheme 1, b). In addition, the competition of [3+2] and [2+2] cycloadditions remains the third one. Thus far, none of the reaction through a particular starting material aimed to tackle all these challenges has been reported. Herein, we present novel examples on the controllable [3+2] and [2+2] cycloaddition of indolylallenes 1, affording divergent synthesis of indole-fused heterocycles 2, 3 and 4: the all-carbon quaternary stereocenter in products 2 and 3 could be controlled by employing different Au or Pt catalysts, respectively (Scheme 2, a and b); while the exo-type [2+2] cycloaddition was realized in the presence of [IPrAuCl]/AgNTf2 catalytic system (Scheme 2, c). Scheme 1. Formal intramolecular cycloaddition modes of allenes with indoles
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a) Formal intramolecular [3 + 2] Cycloaddition R1
R1
R2 N
R2
N
Challenge: stereocontrol of the all-carbon quaternary stereocenter. b) Formal intramolecular [2 + 2] Cycloaddition
R1
R1
R1
R N
R2
R2
2
or
N
N
Endo
Exo
Challenge: Regioselective endo or exo [2 + 2] cycloaddition.
Scheme 2. Controllable Au- and Pt-catalyzed cycloaddition of indolyl-allenes
RESULTS AND DICUSSION We first investigated the reaction of N-(2-(1H-indol-1yl)ethyl)-N-(4-cyclopropyl-2-methylbuta-2,3-dien-1-yl)-4methylbenzenesulfonamide 1a in the presence of various catalysts, and the results are summarized in Table 1. Initially, the use of PtCl2 afforded the [3+2] cycloadduct 2a in 86% isolated yield as a single isomer (Table 1, entry 1). Unexpectedly, when [IPrAuCl]/AgNTf2 was employed as the catalyst, the diazabenzo[a]cyclopenta[cd]azulene 3a was obtained in 62% yield along with [2+2] cycloadduct 4a in 25% yield (Table 1, entry 2). Notably, 3a was the epimer of 2a, which aroused our interest in exploring these diverse reaction patterns. Control experiment indicated that AgNTf2 had no catalytic activity in this reaction (Table 1, entry 3). Then, in the presence of [Ph3PAuCl]/AgNTf2, the [2+2] cycloadduct 4a was obtained in 26% yield along with 72% of starting material 1a (Table 1, entry 4). Replacing [Ph3PAuCl]/AgNTf2 with [Me3PAuCl]/AgNTf2 gave similar reaction outcomes (Table 1, entry 5). Subsequent gold catalyst screening revealed that [JohnPhosAuCl]/AgNTf2 exhibited the best catalytic performance, furnishing the desired adduct 3a in 95% yield (Table 1, entries 6-8). Further examination of silver salts disclosed that AgNTf2 was the best choice for the formation of 3a (Table 1, entries 8-10). As expected, the use of [JohnPhosAu]NTf2 produced the corresponding product 3a in 93% isolated yield (Table 1, entry 11). To our delight, the reaction of 1b afforded the desired [2+2] cycloadduct 4b in 85% isolated yield when [IPrAuCl]/AgNTf2 was employed as catalyst (Table 1, entry 12). Thus, the different reaction conditions for selective synthesis of 2, 3 and 4 have been smoothly optimized, respectively (Table 1, entries 1, 11 and 12). The structures of 2a, 3a and 4a have been unequivocally confirmed by X-ray diffrac[9] tion. Table 1. Optimization of conditions for transition-metalcatalyzed cycloaddition reactions
With the optimal reaction conditions in hand, we next sought to expand the substrate scope of this platinumcatalyzed cyclization. As can be seen from Table 2, the substrate scope of this synthetic protocol was broad. For sub1 2 strates 1b-1h bearing various R and R substituents, the reactions proceeded smoothly to deliver the functionalized diazabenzo[a]cyclopenta[cd]azulenes 2b-2h in 54-85% yields (Table 2, entries 1-7); while messy reaction result was observed when substrate 1i was examined, presumably due to 3 the steric hindrance of 2,4,6-trimethylphenyl group (R ) (Table 2, entry 8). Substrate 1j with a longer carbon tether (n = 2) was also suitable for this cycloaddition, giving the desired eight-membered heterocyclic adduct 2j in 79% yield (Table 2, entry 9). At the same time, the corresponding heterocyclic product 2k was also obtained in 79% yield when 1k bearing a NBs group (Bs = 4-bromobenzenesulfonyl) was utilized as the substrate (Table 2, entry 10). Substrate 1l with oxygen linker provided the desired adducts 2l in 30% yield (Table 2, entry 11), while 1m with carbon linker gave messy reaction result (Table 2, entry 12). In the cases of substrates 1n-1q, the 3 electronic properties of R had no significant impact on the reaction outcomes and the desired cycloadducts 2n-2q were furnished in 60-72% yields (Table 2, entries 13-15). Furthermore, the formation of epimeric product 3a in the presence of [JohnPhosAu]NTf2 inspired us to explore the substrate generality, and the results are exhibited in Table 3. Among a diverse array of tosylamide-linked substrates 1b-1h 1 2 (X = NTs), different R and R groups were tested, giving the desired [3+2] annulation products 3b-3h in 23-74% yields along with the [2+2] cycloadducts 4b-4h in 13-54% yields (Table 3, entries 1-7); while for substrate 1i bearing a large 3 2,4,6-trimethylphenyl group (R ), the [3+2] cycloadduct 3i was obtained in 21% yield along with 71% of starting material 1i (Table 3, entry 8). As for substrate 1j, the corresponding eight-membered heterocyclic product 3j was delivered in 88% yield (Table 3, entry 9). Moreover, for substrate 1k with X as NBs anchor, the corresponding product 3k was obtained in 91% yield (Table 3, entry 10); while substrates 1l and 1m with oxygen and carbon linkers provided the desired adducts 3l and 3m successfully as well, albeit in relatively low yields
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(Table 3, entries 11-12). In addition, substrates 1n and 1r-1u 3 with a series of substituents on the indole ring (R ) were also well-tolerated, furnishing the corresponding diazabenzo[a]cyclopenta[cd]azulenes 3n-3r in 88-96% yields (Table 3, entries 13-17).
Table 4. Scope of Au-catalyzed [2+2] cycloaddition
Table 2. Substrate scope for Pt-catalyzed [3+2] cyclization
Furthermore, under the standard conditions, different reaction pathways could occur when substrates 1v and 1w were utilized. As shown in Scheme 3, as for substrate 1v, in which the indole functional group was replaced by a pyrrole group, [10] took place an intramolecular Friedel-Crafts reaction smoothly, providing the seven-membered diazoheterocyclic [9] ring product 5 in 95% yield. At the same time, when substrate 1w with a phenyl group on the allene moiety was em[10] ployed, a varied intramolecular Friedel-Crafts reaction between the phenyl group and the allene moiety took place, [9] affording the corresponding product 6 in 93% yield. Table 3. Substrate scope for Au-catalyzed [3+2] cycloaddition
Notably, in the presence of [IPrAuCl]/AgNTf2, the alternative [2+2] cyclizations could be exclusively achieved with a broad substrate scope (Table 4). Accordingly, the intriguing eight-membered diazoheterocyclic ring compounds 4b-4k 1 3 with a diverse array of R and R groups could be easily obtained in 74%-94% yields.
Scheme 3. Different pathways of other substrates 1 under the standard conditions
To illustrate the synthetic utility, several transformations of product 3 were conducted (Scheme 4). Interestingly, a Rhcomplex 7 was obtained in 85% yield upon treatment of 3a o with [Rh(CO)2Cl]2 in THF at 60 C. 3a could also be transformed into compound 8 in 73% yield through a conjugate addition with HOTf (trifluoromethanesulfonic acid) and MVK (methyl vinyl ketone) in DCM. Moreover, a one-pot [9] tandem reaction to transform 1a into compound 9 could be realized in 52% yield in the presence of [JohnPhosAu]NTf2 and followed by treatment with HOTf and CH3CN (for more related transformations of 3, see Scheme SI-1 in the Supporting Information). Scheme 4. Transformations of product 3a
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Scheme 6. Control experiments a)
PtCl2 (5 mol%) Me
.
N
>95% 1x was recovered
4Å MS, DCE, 70 oC, 12 h Me
Me
Me
[JohnPhosAu]NTf 2 (5 mol%)
NTs
4Å MS, DCE, 70 oC, 6 h
1x
N
NTs
3s, 70% yield b)
Pt(COD)Cl2 (5 mol%)
R
>95% 1a was recovered
4Å MS, DCE, 70 oC, 12 h
. Me
N
Pt(PPh3)2Cl2 (5 mol%)
NTs
>95% 1a was recovered
4Å MS, DCE, 70 oC, 12 h
1a: R = cyclopropyl
c) In situ 1H NMR spectroscopic studies R
R Pt Condition A: [Pt]
To verify the Au- and Pt-catalyzed [3+2] cycloaddition reaction pathways, deuterium labeling experiments were performed as shown in Scheme 5. First, treating 1a with PtCl2 or o [JohnPhosAu]NTf2 at 70 C in the presence of D2O (20.0 equiv), deuterated products [D]-2a and [D]-3a could be formed, suggesting the formation of metallo-carbon inter[11] mediate (Scheme 5, a and b). While conducting the reaco tions at 25 C (room temperature), PtCl2 showed very low catalytic activity (Scheme 5, a). In gold catalysis, 3a was obtained in 40% yield but with no deuterium corporation at 25 o C, indicating that gold complex prefers to coordination with allene moiety instead of C-3 metallation of indole (Scheme 5, b). Then, by using [D]-1a in the presence of Pt and Au catalysts, the corresponding adducts [D]-2a and [D]-3a were obtained in 85% yield with 42% D and 93% yield with 49% D o content at 70 C, respectively (Scheme 5, c). Furthermore, the different reaction results of substrate 1i under Pt or Au catalysis also revealed that there might be two different reaction mechanisms (Table 2, entry 8 vs Table 3, entry 8). Scheme 5. Isotopic Labeling Experiments a)
R
R D
. N
Me NTs
PtCl2 (5 mol%) D2O (20.0 equiv) DCE, 3 h
1a: R = cyclopropyl 70 oC rt
R D
Me NTs +
.
Me NTs [D]-1a 48% yield 43% yield D content: 44% D content: 91% trace, >99% 1a was recovered N
N
[D]-2a
b)
R Me
D [JohnPhosAu]NTf2 (5 mol%)
NTs +
N
D2O (20.0 equiv) DCE, 70 oC, 0.5 h
[D]-1a, 36% yield D content: 68%
[D]-3a, 57% yield D content: 33%
1a
R Me
[JohnPhosAu]NTf2 (5 mol%) D2O (20.0 equiv) DCE, rt, 1 h
N
NTs + 1a, 53% yield
3a, 40% yield c) R D
.
N
PtCl2 (5 mol%) 4Å MS, DCE, 70 oC, 12 h
[D]-2a, 85% yield D content: 42%
Me NTs
[D]-1a, D content: 91%
[JohnPhosAu]NTf2 (5 mol%) 4Å MS, DCE, 70 oC, 6 h
[D]-3a, 93% yield D content: 49%
N
R
Me Me
N
NTs
NTs
. N
.
2a, 81% yield
Not observed Me
R
R
NTs
Au
Condition B: [Au]
1a: R = cyclopropyl
Me
.
N
N
Me NTs
NTs
3a, 90% yield
Not observed Condition A: [Pt] N
N
Ts N
Ph
10 was recovered
Ph
10 was recovered
Pt Not observed
Ph
10
Ts N
Condition C: [Au] N
Ts N
Au Not observed Condition A: PtCl2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 2 h Condition B: [JohnPhosAu]NTf2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 0.5 h Condition C: [JohnPhosAu]NTf2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 2 h
To further verify these cycloaddition reaction mechanisms, several control experiments were also performed and the results are shown in Scheme 6. First, when substrate 1x with a methyl substituent at the C3 position of indole ring was examined under the standard reaction conditions, no desired product was detected in the presence of PtCl2, while cycloadduct 3s was obtained in 70% yield under gold catalysis, which suggested the different catalytic behavior of Pt and Au catalysts (Scheme 6, a). Then, when substrate 1a was examined by employing Pt(COD)Cl2 or Pt(PPh3)2Cl2 as the catalyst, no desired product was obtained, probably due to the steric effect of catalysts (Scheme 6, b). Furthermore, we have also treated substrate 1a and the newly synthesized substrate 10 with stoichiometric PtCl2 or [JohnPhosAu]NTf2 in nuclear magnetic tubes respectively, so as to find direct evidence of the corresponding metallo-carbon intermediates (Scheme 6, c). However, no metallo-carbon intermediate was observed 1 through H NMR spectroscopic analysis in the nuclear mago netic resonance spectrometer at 70 C, presumably due to that the equilibrium largely leans to the starting materials 1a or 10 with metal catalyst and very trace of the metallo-carbon intermediate was formed (see SI-151~SI-154 in the Supporting Information). At the same time, the desired adducts 2a and 3a were obtained in 81% yield and 90% yield, respectively
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when substrate 1a was examined (for more information, see SI-155 in the Supporting Information). Although the full mechanistic details of these transformations remain to be elucidated, plausible mechanisms for the reactions are outlined in Scheme 7 on the basis of the above deuterium labeling and control experiments and pre[2], [3], [4], [11], [12] vious reports to date. For [3+2] annulation, both Pt and gold can form a metallo-carbon intermediate A via reversible C-3 metallation of indole. The following cisaddition to give heterocycle B only takes place when PtCl2 is used presumably due to that gold complexes are sterically hindered. The lack of catalytic activity of Pt(COD)Cl2 and Pt(PPh3)2Cl2 are in accordance with this proposal as well. Then, a Pt-carbene intermediate C is generated, following by 1,2-hydride migration and regeneration of catalyst to yield product 2. As for gold-catalyzed reactions, the coordination of gold complex with allene is a dominant process, though the formation of intermediate A is possible. The intramolecular nucleophilic attack of indole (C3) onto the Au-activated allene A’ forms the alkenylgold(I) complex B’, which diverges into different products. On one hand, similar to Pt catalysis, the desired adducts 3 is formed by tandem cyclization, hydride migration and elimination process through Au-carbene intermediate C’ and alkenylgold(I) complex D’ (path a). The all-carbon quaternary stereocenters in products 2 and 3 were stereoselectively constructed presumably due to the different E and Z configuration of alkenylmetal complexes B and B’. On the other hand, cyclobutane compound 4 is formed via nucleophilic trap of iminum intermediate by C-Au bond 1 (path b). Substrates with cyclopropyl group (R ) tend to give [3+2] cycloadducts 3 probably because the three-membered ring can significantly stabilize the cationic intermediate D’; 2 while substrates with a larger R group disfavored the formation of metal-carbene intermediate C or C’, which led to lower yield of 2 and 3. In addition, the ligands of gold com1 plex as well as the steric and electronic properties of R and 2 R groups make a combined influence on the selective formation of 3 and 4. Scheme 7. Proposed mechanisms for Au- and Pt-catalyzed cycloadditions
CONCLUSION We have disclosed the catalyst-dependent stereodivergent and regioselective synthesis of indole-fused tricyclic system with several contiguous stereocenters through formal cycloadditions of indolyl-allenes in an atom-economical way. The reaction features total reversion of an all-carbon quaternary stereocenter when gold or platinum complex was employed as the catalyst through [3+2] cycloaddition of allene with indole, affording different diazabenzo[a]cyclopenta[cd]azulenes as epimers, respectively. In addition, in the presence of IPrAuCl and AgNTf2, highly regioselective exo-type [2+2] cycloaddition was observed, in which allene moiety acted as a 2C synthon. Different reaction mechanisms have been also proposed on the basis of deuterium labeling experiments. Further investigations on expanding the scope of this reaction towards a variety of novel and potentially useful polycyclic compounds as well as the applications of this protocol to natural product synthesis are in progress.
EXPERIMENTAL SECTION General procedure for the synthesis of product 2: To a flame dried Schlenk tube was added indolyl-allene 1 (0.1 mmol), PtCl2 (0.005 mmol, 5 mol%), 50 mg 4Å MS and the anhydrous solvent DCE (1.0 mL) under argon. Then, the reo sulting solution was allowed to stir at 70 C for 12 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the desired product 2. Compound 2a. A white solid, 86% yield (36 mg). M.p.: 175o 1 178 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.45-0.51 (m, 1H,
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CH2), 0.61-0.67 (m, 1H, CH2), 0.72 (s, 3H, CH3), 0.75-0.88 (m, 2H, CH2), 1.50-1.58 (m, 1H, CH), 2.42 (s, 3H, CH3), 2.46 (dd, J = 11.6 Hz, 11.6 Hz, 1H, CH2), 3.16 (dd, J = 11.6 Hz, 15.6 Hz, 1H, CH2), 3.50 (dd, J = 11.6 Hz, 12.4 Hz, 1H, CH2), 3.61 (dd, J = 4.0 Hz, 12.4 Hz, 1H, CH2), 3.85 (dd, J = 11.6 Hz, 11.6 Hz, 1H, CH2), 4.05 (d, J = 8.8 Hz, 1H, CH), 4.18 (d, J = 8.8 Hz, 1H, CH), 4.25 (dd, J = 4.0 Hz, 15.6 Hz, 1H, CH2), 5.10 (s, 1H, =CH), 6.28 (d, J = 7.6 Hz, 1H, ArH), 6.64 (dd, J = 7.6 Hz, 7.6 Hz, 1H, ArH), 7.08 (dd, J = 7.6 Hz, 7.6 Hz, 1H, ArH), 7.18 (d, J = 7.6 Hz, 1H, ArH), 7.31 (d, J = 8.0 Hz, 2H, ArH), 7.66 (d, J = 8.0 Hz, 2H, 13 ArH). C NMR (CDCl3, 100 MHz, TMS) δ 5.9, 7.9, 11.7, 21.5, 23.6, 46.3, 48.3, 52.6, 54.2, 57.6, 74.7, 105.0, 117.3, 123.8, 126.9, 127.5, 128.0, 129.76, 129.8, 136.4, 143.3, 147.0, 152.2. IR (CH2Cl2) ν 3033, 2922, 2852, 1728, 1601, 1481, 1456, 1378, 1331, 1303, 1281, 1249, 1234, 1184, 1156, 1118, 1091, 1073, 1019, 1003, 974, 924, 906, -1 876, 814, 765, 733, 708, 699, 660 cm . HRMS (ESI) Calcd. for +1 + C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1943.
(m, 2H, CH2), 3.66 (dd, J = 3.2 Hz, 8.4 Hz, 1H, CH), 3.86 (ddd, J = 2.8 Hz, 4.4 Hz, 7.6 Hz, 1H, CH2), 4.23 (d, J = 17.2 Hz, 1H, CH2), 5.14 (d, J = 8.4 Hz, 1H, CH), 6.29 (d, J = 8.0 Hz, 1H, ArH), 6.57 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 6.99-7.04 (m, 2H, ArH), 13 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.72 (d, J = 8.4 Hz, 2H, ArH). C NMR (CDCl3, 75 MHz, TMS) δ 3.1, 6.1, 15.8, 16.6, 21.8, 45.1, 45.7, 52.0, 54.4, 56.6, 64.8, 105.9, 117.2, 124.9, 126.9, 127.4, 128.0, 130.1, 132.5, 135.7, 139.3, 143.8, 151.9. IR (CH2Cl2) ν 3044, 2922, 2842, 1726, 1603, 1486, 1459, 1444, 1376, 1357, 1338, 1267, 1184, -1 1158, 1111, 1090, 1013, 917, 876, 815, 737, 706, 655 cm . HRMS +1 + (ESI) Calcd. for C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1947.
General procedure for the synthesis of products 3, 5 and 6: To a flame dried Schlenk tube was added indolyl-allene 1 (0.1 mmol), [JohnPhosAu]NTf2 (0.005 mmol, 5 mol%), 50 mg 4Å MS and the anhydrous solvent DCE (1.0 mL) under argon. o Then, the resulting solution was allowed to stir at 70 C for 6 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the desired cycloadducts 3, 5 or 6.
Experimental procedures, characterization data, NMR spectra, and crystallographic data (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.
Compound 3a. A white solid, 93% yield (39 mg). M.p.: 130-133 o 1 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.32-0.43 (m, 2H, CH2), 0.65-0.73 (m, 2H, CH2), 1.28-1.36 (m, 4H, CH, CH3), 2.41 (s, 3H, CH3), 2.53 (d, J = 13.2 Hz, 1H, CH2), 2.60 (ddd, J = 2.4 Hz, 12.0 Hz, 14.4 Hz, 1H, CH2), 3.16 (ddd, J = 2.4 Hz, 12.0 Hz, 14.4 Hz, 1H, CH2), 3.54 (d, J = 13.2 Hz, 1H, CH2), 3.75 (dd, J = 14.4 Hz, 14.4 Hz, 1H, CH2), 3.83 (dd, J = 12.0 Hz, 12.0 Hz, 1H, CH2), 3.88 (d, J = 8.4 Hz, 1H, CH), 4.40 (d, J = 8.4 Hz, 1H, CH), 4.84 (s, 1H, =CH), 6.26 (d, J = 8.0 Hz, 1H, ArH), 6.60 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 7.02 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.29 (d, J = 8.0 Hz, 2H, ArH), 7.64 (d, 13 J = 8.0 Hz, 2H, ArH). C NMR (CDCl3, 75 MHz, TMS) δ 6.8, 7.4, 9.8, 21.7, 25.2, 50.1, 51.2, 55.0, 55.6, 57.5, 79.8, 105.5, 117.1, 125.0, 126.8, 127.4, 128.0, 129.3, 130.0, 135.3, 143.6, 147.0, 150.5. IR (CH2Cl2) ν 3022, 2919, 2842, 1730, 1601, 1484, 1452, 1369, 1336, 1288, 1272, 1189, 1160, 1129, 1089, 1013, 957, 942, 904, 870, -1 814, 737, 723, 661 cm . HRMS (ESI) Calcd. for +1 + C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1945. General procedure for the synthesis of product 4: A solution of [IPrAuCl] (0.005 mmol, 5 mol %) and AgNTf2 (0.005 mmol, 5 mol %) in DCE (0.5 mL) was stirred at room temperature under argon atmosphere for 15 minutes. To the solution was added a solution of indolyl-allenes 1 (0.1 mmol) in o DCE (0.5 mL), and the reaction mixture was stirred at 70 C for 12 h. The mixture was concentrated in vacuo to yield the crude product, which was purified by flash chromatography on silica gel to furnish the desired adduct 4 as a solid. Compound 4a. A white solid, 26% yield (11 mg). M.p.: 131-134 1 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.19-0.31 (m, 2H, CH2), 0.50-0.65 (m, 2H, CH2), 1.06-1.12 (m, 1H, CH), 1.48 (s, 3H, CH3), 2.38-2.45 (m, 4H, CH, CH3), 2.69 (ddd, J = 3.6 Hz, 7.6 Hz, 11.6 Hz, 1H, CH2), 2.96 (d, J = 17.2 Hz, 1H, CH2), 3.44-3.48 o
ASSOCIATED CONTENT Supporting Information
AUTHOR INFORMATION Corresponding Author [email protected]; [email protected], Fax 86-21-64166128 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for the financial support from the National Basic Research Program of China (973)2015CB856603, Shanghai Municipal Committee of Science and Technology (11JC1402600), and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203 and 20732008).
REFERENCES (1) For selected reviews, see: (a) Sundberg, R. J. Indoles, Academic Press, San Diego 1996. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (d) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9608. (e) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (f) Gazit, A.; Osherov, N.; Posner, I.; Yaish, P.; Poradosu, E.; Gilon, C.; Levitzki, A. J. Med. Chem. 1991, 34, 1896. (g) Pajouhesh, H.; Parsons, R.; Popp, F. D. J. Pharm. Sci. 1983, 72, 318. (h) Finefield, J. M.; Frisvad, J. C.; Sherman, D. H.; Williams, R. M. J. Nat. Prod. 2012, 75, 812. (i) Yang, J.; Wearing, X. Z.; Le Quesne, P. W.; Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2008, 71, 1431. (j) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666. (k) Duan, S.-W.; Li, Y.; Liu, Y.Y.; Zou, Y.-Q.; Shi, D.-Q.; Xiao, W.-J. Chem. Commun. 2012, 48, 5160. (l) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1998, 63, 4481. (m) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63. (n) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086. (o) Ding, K.; Lu, Y.; NikolovskaColeska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432. (p) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (q) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41,
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7247. (r) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (s) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127. (t) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (2) (a) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12. (b) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067. (c) Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (d) Ma, S. Chem. Rev. 2005, 105, 2829. (e) Modern Allene Chemistry (Eds.: Krause, N.; Hashmi, A. S. K.), Wiley-VCH, Weinheim, 2004. (f) Bhunia, S.; Liu, R.-S. Pure Appl. Chem. 2012, 84, 1749. (g) Gulías, M.; López, F.; Mascareñas, J. L. Pure Appl. Chem. 2011, 83, 495. (h) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (i) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (j) Lee, J. H.; Toste, F. D. Angew. Chem. Int. Ed. 2007, 46, 912. (k) Lemière, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.; Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (l) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem. Int. Ed. 2007, 46, 909. (m) Trillo, B.; López, F.; Gulías, M.; Castedo, L.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2008, 47, 951. (n) Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6348. (o) Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. Chem. Eur. J. 2009, 15, 3336. (p) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692. (q) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; Fürstner, A. Angew. Chem. Int. Ed. 2010, 49, 2542. (r) Alonso, I.; Faustino, H.; López, F.; Mascareñas, J. Angew. Chem. Int. Ed. 2011, 50, 11496. (s) Rao, W.; Sally; Berry, S. N.; Chan, P. W. H. Chem. Eur. J. 2014, 20, 13174. (t) Hashmi, A. S. K.; Schwarz, L.; Choi, J.; Frost, T. M. Angew. Chem. Int. Ed. 2000, 39, 2285. (u) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2000, 39, 3590. (v) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (w) Suresh, R. R.; Swamy, K. C. K. J. Org. Chem. 2012, 77, 6959. (x) Wang, M.-Z.; Zhou, C.-Y.; Guo, Z.; Wong, E. L.-M.; Wong, M.-K.; Che, C.-M. Chem. Asian J. 2011, 6, 812. (3) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (4) Zhang, G.; Catalano, V. J.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 11358. (5) (a) Luzung, M. R.; Mauleón, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402. (b) Alonso, I.; Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. J. Am. Chem. Soc. 2009, 131, 13020. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783. (6) (a) Huang, L.; Yang, H.-B.; Zhang, D.-H.; Zhang, Z.; Tang, X.-Y.; Xu, Q.; Shi, M. Angew. Chem. Int. Ed. 2013, 52, 6767. (b) Zhang, Z.; Tang, X.; Xu, Q.; Shi, M. Chem. Eur. J. 2013, 19, 10625. (7) For a selection of reviews, see: (a) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96, 635. (c) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813. (d) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev. 2004, 33, 431. (e) Echavarren, A. M.; Mendez, M.; Munoz, M. P.; Nevado, C.; Martin-Matute, B.; Nieto-Ober-huber, C.; Cardenas, D. J. Pure Appl. Chem. 2004, 76, 453. (f) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271. (g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (h) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (i) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (j) Jiménez-Núñez, E. S.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (k) Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem. Int. Ed. 2008, 47, 4268. (l) Sohel, S. M. A.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269. (m) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (n) Shu, X.-Z.; Shu, D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev. 2012, 41, 7698. (o) Garayalde, D.; Nevado, C. ACS Catal. 2012, 2, 1462. (p) Bongers, N.; Krause, N. Angew. Chem. Int. Ed. 2008, 47, 2178. (q) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (r) Corma, A.; Leyva-Pérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (s) Arcadi, A. Chem. Rev. 2008, 108, 3266. (t) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (8) For selected examples of gold or platinum-catalyzed reactions, see: (a) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (b) Watson, D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056. (c) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802. (d) Wang, S.; Zhang, L. J. Am. Chem. Soc.
2006, 128, 14274. (e) Marion, N.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2750. (f) Bolte, B.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010, 132, 7294. (g) Wetzel, A.; Gagosz, F. Angew. Chem. Int. Ed. 2011, 50, 7354. (h) Hashmi, A. S. K.; Yang, W. B.; Yu, Y.; Rominger, F. Chem. Eur. J. 2012, 18, 6576. (i) Hashmi, A. S. K. Wieteck, M.; Braun, I.; Rudolph, M.; Rominger, F. Angew. Chem. Int. Ed. 2012, 51, 10633. (j) Hansmann, M. M.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 2593. (k) Cheong, P. H.; Morganelli, P.; Luzung, M. R.; Houk, K. N.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517. (l) Marion, N.; Lemière, G.; Correa, A.; Costabile, C.; Ramón, R. S.; Moreau, X.; Frémont, P.; Dahmane, R.; Hours, A.; Lesage, D.; Tabet, J.; Goddard, J.; Gandon, V.; Cavallo, L.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. Eur. J. 2009, 15, 3243. (m) Gawade, S. A.; Bhunia, S.; Liu, R.-S. Angew. Chem. Int. Ed. 2012, 51, 7835. (n) Song, X.-R.; Xia, X.-F.; Song, Q.-B.; Yang, F.; Li, Y.-X.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2012, 14, 3344. (o) Brazeau, J.-F.; Zhang, S. Y.; Colomer, I.; Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 2742. (p) Raducan, M.; Moreno, M.; Boura, C.; Echavarren, A. M. Chem. Commun. 2012, 48, 52. (q) Zheng, H. J.; Huo, X.; Zhao, C. G.; Jing, P.; Yang, J.; Fang, B. W.; She, X. G. Org. Lett. 2011, 13, 6448. (r) Hashmi, A. S. K.; Yang, W. B.; Yu, Y.; Hansmann, M. M.; Rudolph, M.; Rominger, F. Angew. Chem. Int. Ed. 2013, 52, 1329. (s) Hashmi, A. S. K.; Wieteck, M.; Braun, I.; Nosel, P.; Jongbloed, L.; Rudolph, M.; Rominger, F. Adv. Synth. Catal. 2012, 354, 555. (9) The structures of 2a, 3a, 4a and 5-9 have been confirmed by Xray diffraction and their CIF data are shown in the Supporting Information. (10) (a) Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352. (b) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (c) Tarselli, M. A.; Gagné, M. R.; J. Org. Chem. 2008, 73, 2439.
(11) (a) Kaminskaia, N. V.; Ullmann, G. M.; Fulton, D. B.; Kostic, N. M. Inorg. Chem. 2000, 39, 5004. (b) Fürstner, A.; Aïssa, C. J. Am. Chem. Soc. 2006, 128, 6306. (c) Chianese, A. R.; Lee, S. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2007, 46, 4042. (d) Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007, 46, 3410. (e) Sokol, J. G.; Korapala, C. S.; White, P. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2011, 50, 5658. (f) Mullen, C. A.; Campbell, A. N.; Gagné, M. R. Angew. Chem. Int. Ed. 2008, 47, 6011. (g) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208. (h) Mullen, C. A.; Gagné, M. R. J. Am. Chem. Soc. 2007, 129, 11880. (i) Chen, J.-T.; Hsu, R.-H.; Chen, A.-J. J. Am. Chem. Soc. 1998, 120, 3243. (j) Cochrane, N. A.; Nguyen, H.; Gagné, M. R. J. Am. Chem. Soc. 2013, 135, 628. (k) Koh, J. H.; Larsen, A. O.; Gagné, M. R. Org. Lett. 2001, 3, 1233. (l) Kerber, W. D.; Koh, J. H.; Gagné, M. R. Org. Lett. 2004, 6, 3013. (12) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2010, 49, 5232.
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Catalyst-dependent Stereodivergent and Regioselective Synthesis of Indole-fused Heterocycles through Formal Cycloadditions of Indolyl-allenes Liang-Yong Mei, Yin Wei, Xiang-Ying Tang, and Min Shi J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2015 Downloaded from http://pubs.acs.org on June 6, 2015
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Catalyst-dependent Stereodivergent and Regioselective Synthesis of Indole-fused Heterocycles through Formal Cycloadditions of Indolyl-allenes Liang-Yong Mei,‡ Yin Wei,† Xiang-Ying Tang,†* Min Shi† ‡* †
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Lu, Shanghai 200032, China. ‡ Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Meilong Road No. 130, Shanghai 200237, China. Supporting Information ABSTRACT: Stereo- and regioselective construction of poly-heterocycles, especially those with several contiguous stereocenters, is still a challenge. In this paper, catalyst-dependent stereodivergent and regioselective synthesis of indole-fused heterocycles through formal cycloadditions of indolyl-allenes have been developed. The reaction features total reversion of an all-carbon quaternary stereocenter when gold or platinum complex was employed as the catalyst through [3+2] cycloaddition of allene with indole, affording different diazabenzo[a]cyclopenta[cd]azulenes as epimers, respectively. In addition, in the presence of IPrAuCl and AgNTf2, highly regioselective exo-type [2+2] cycloaddition was observed, in which allene served as a 2C synthon. This methodology provides a simple and straightforward approach for the construction of indole-fused tricyclic systems under mild conditions in an atom-economical way.
INTRODUCTION Indole fused poly-heterocycles, as constituents of diverse natural alkaloids and pharmaceutical agents, have drawn much attention of organic and bioorganic chemists during [1] the past several decades. In the realm on the development of synthetic methodology towards such compounds, intramolecular cycloaddition of allene as a 3C or 2C synthon with indole is a viable strategy to achieve this goal. Indeed, several elegant works have been done using allenes as three-carbon components in transition-metal-catalyzed [3+n] cycloaddi[2] tion. For instance, Gagosz and coworkers started the pioneering work by reporting a formal Au-catalyzed [3+2] intramolecular cyclization of enynyl acetates, which went [3] through allenyl ester intermediates. Zhang et al. showed a Pt-catalyzed [3+2] annulation of allenyl esters generated in [4] situ via a 3,3-rearrangement of propargyl precursors. Additionally, under varied reaction conditions, the alternative [2+2] and [4+2] cycloadditions could be selectively induced, in which the employed allenes reacted with other substances [5] through one of the two double bonds. Based on these elegant studies as well as our ongoing efforts in exploring novel [6] synthetic routes for indole-fused scaffolds, we envisaged that indolyl-allene substrates 1 could undergo a certain cy[7], [8] cloaddition under Au- or Pt catalysis. However, due to the multiple reactive sites of allenes, there are several significant challenges to realize the desired reaction with respect to chemo- and stereoselectivity. As for the
intramolecular [3+2] cycloaddition, to stereocontrol the allcarbon quaternary stereocenter is very difficult (Scheme 1, a). Moreover, it is also troublesome to regioselectively control the endo- or exo-type in [2+2] cycloaddition (Scheme 1, b). In addition, the competition of [3+2] and [2+2] cycloadditions remains the third one. Thus far, none of the reaction through a particular starting material aimed to tackle all these challenges has been reported. Herein, we present novel examples on the controllable [3+2] and [2+2] cycloaddition of indolylallenes 1, affording divergent synthesis of indole-fused heterocycles 2, 3 and 4: the all-carbon quaternary stereocenter in products 2 and 3 could be controlled by employing different Au or Pt catalysts, respectively (Scheme 2, a and b); while the exo-type [2+2] cycloaddition was realized in the presence of [IPrAuCl]/AgNTf2 catalytic system (Scheme 2, c). Scheme 1. Formal intramolecular cycloaddition modes of allenes with indoles
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a) Formal intramolecular [3 + 2] Cycloaddition R1
R1
R2 N
R2
N
Challenge: stereocontrol of the all-carbon quaternary stereocenter. b) Formal intramolecular [2 + 2] Cycloaddition
R1
R1
R1
R N
R2
R2
2
or
N
N
Endo
Exo
Challenge: Regioselective endo or exo [2 + 2] cycloaddition.
Scheme 2. Controllable Au- and Pt-catalyzed cycloaddition of indolyl-allenes
RESULTS AND DICUSSION We first investigated the reaction of N-(2-(1H-indol-1yl)ethyl)-N-(4-cyclopropyl-2-methylbuta-2,3-dien-1-yl)-4methylbenzenesulfonamide 1a in the presence of various catalysts, and the results are summarized in Table 1. Initially, the use of PtCl2 afforded the [3+2] cycloadduct 2a in 86% isolated yield as a single isomer (Table 1, entry 1). Unexpectedly, when [IPrAuCl]/AgNTf2 was employed as the catalyst, the diazabenzo[a]cyclopenta[cd]azulene 3a was obtained in 62% yield along with [2+2] cycloadduct 4a in 25% yield (Table 1, entry 2). Notably, 3a was the epimer of 2a, which aroused our interest in exploring these diverse reaction patterns. Control experiment indicated that AgNTf2 had no catalytic activity in this reaction (Table 1, entry 3). Then, in the presence of [Ph3PAuCl]/AgNTf2, the [2+2] cycloadduct 4a was obtained in 26% yield along with 72% of starting material 1a (Table 1, entry 4). Replacing [Ph3PAuCl]/AgNTf2 with [Me3PAuCl]/AgNTf2 gave similar reaction outcomes (Table 1, entry 5). Subsequent gold catalyst screening revealed that [JohnPhosAuCl]/AgNTf2 exhibited the best catalytic performance, furnishing the desired adduct 3a in 95% yield (Table 1, entries 6-8). Further examination of silver salts disclosed that AgNTf2 was the best choice for the formation of 3a (Table 1, entries 8-10). As expected, the use of [JohnPhosAu]NTf2 produced the corresponding product 3a in 93% isolated yield (Table 1, entry 11). To our delight, the reaction of 1b afforded the desired [2+2] cycloadduct 4b in 85% isolated yield when [IPrAuCl]/AgNTf2 was employed as catalyst (Table 1, entry 12). Thus, the different reaction conditions for selective synthesis of 2, 3 and 4 have been smoothly optimized, respectively (Table 1, entries 1, 11 and 12). The structures of 2a, 3a and 4a have been unequivocally confirmed by X-ray diffrac[9] tion. Table 1. Optimization of conditions for transition-metalcatalyzed cycloaddition reactions
With the optimal reaction conditions in hand, we next sought to expand the substrate scope of this platinumcatalyzed cyclization. As can be seen from Table 2, the substrate scope of this synthetic protocol was broad. For sub1 2 strates 1b-1h bearing various R and R substituents, the reactions proceeded smoothly to deliver the functionalized diazabenzo[a]cyclopenta[cd]azulenes 2b-2h in 54-85% yields (Table 2, entries 1-7); while messy reaction result was observed when substrate 1i was examined, presumably due to 3 the steric hindrance of 2,4,6-trimethylphenyl group (R ) (Table 2, entry 8). Substrate 1j with a longer carbon tether (n = 2) was also suitable for this cycloaddition, giving the desired eight-membered heterocyclic adduct 2j in 79% yield (Table 2, entry 9). At the same time, the corresponding heterocyclic product 2k was also obtained in 79% yield when 1k bearing a NBs group (Bs = 4-bromobenzenesulfonyl) was utilized as the substrate (Table 2, entry 10). Substrate 1l with oxygen linker provided the desired adducts 2l in 30% yield (Table 2, entry 11), while 1m with carbon linker gave messy reaction result (Table 2, entry 12). In the cases of substrates 1n-1q, the 3 electronic properties of R had no significant impact on the reaction outcomes and the desired cycloadducts 2n-2q were furnished in 60-72% yields (Table 2, entries 13-15). Furthermore, the formation of epimeric product 3a in the presence of [JohnPhosAu]NTf2 inspired us to explore the substrate generality, and the results are exhibited in Table 3. Among a diverse array of tosylamide-linked substrates 1b-1h 1 2 (X = NTs), different R and R groups were tested, giving the desired [3+2] annulation products 3b-3h in 23-74% yields along with the [2+2] cycloadducts 4b-4h in 13-54% yields (Table 3, entries 1-7); while for substrate 1i bearing a large 3 2,4,6-trimethylphenyl group (R ), the [3+2] cycloadduct 3i was obtained in 21% yield along with 71% of starting material 1i (Table 3, entry 8). As for substrate 1j, the corresponding eight-membered heterocyclic product 3j was delivered in 88% yield (Table 3, entry 9). Moreover, for substrate 1k with X as NBs anchor, the corresponding product 3k was obtained in 91% yield (Table 3, entry 10); while substrates 1l and 1m with oxygen and carbon linkers provided the desired adducts 3l and 3m successfully as well, albeit in relatively low yields
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(Table 3, entries 11-12). In addition, substrates 1n and 1r-1u 3 with a series of substituents on the indole ring (R ) were also well-tolerated, furnishing the corresponding diazabenzo[a]cyclopenta[cd]azulenes 3n-3r in 88-96% yields (Table 3, entries 13-17).
Table 4. Scope of Au-catalyzed [2+2] cycloaddition
Table 2. Substrate scope for Pt-catalyzed [3+2] cyclization
Furthermore, under the standard conditions, different reaction pathways could occur when substrates 1v and 1w were utilized. As shown in Scheme 3, as for substrate 1v, in which the indole functional group was replaced by a pyrrole group, [10] took place an intramolecular Friedel-Crafts reaction smoothly, providing the seven-membered diazoheterocyclic [9] ring product 5 in 95% yield. At the same time, when substrate 1w with a phenyl group on the allene moiety was em[10] ployed, a varied intramolecular Friedel-Crafts reaction between the phenyl group and the allene moiety took place, [9] affording the corresponding product 6 in 93% yield. Table 3. Substrate scope for Au-catalyzed [3+2] cycloaddition
Notably, in the presence of [IPrAuCl]/AgNTf2, the alternative [2+2] cyclizations could be exclusively achieved with a broad substrate scope (Table 4). Accordingly, the intriguing eight-membered diazoheterocyclic ring compounds 4b-4k 1 3 with a diverse array of R and R groups could be easily obtained in 74%-94% yields.
Scheme 3. Different pathways of other substrates 1 under the standard conditions
To illustrate the synthetic utility, several transformations of product 3 were conducted (Scheme 4). Interestingly, a Rhcomplex 7 was obtained in 85% yield upon treatment of 3a o with [Rh(CO)2Cl]2 in THF at 60 C. 3a could also be transformed into compound 8 in 73% yield through a conjugate addition with HOTf (trifluoromethanesulfonic acid) and MVK (methyl vinyl ketone) in DCM. Moreover, a one-pot [9] tandem reaction to transform 1a into compound 9 could be realized in 52% yield in the presence of [JohnPhosAu]NTf2 and followed by treatment with HOTf and CH3CN (for more related transformations of 3, see Scheme SI-1 in the Supporting Information). Scheme 4. Transformations of product 3a
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Scheme 6. Control experiments a)
PtCl2 (5 mol%) Me
.
N
>95% 1x was recovered
4Å MS, DCE, 70 oC, 12 h Me
Me
Me
[JohnPhosAu]NTf 2 (5 mol%)
NTs
4Å MS, DCE, 70 oC, 6 h
1x
N
NTs
3s, 70% yield b)
Pt(COD)Cl2 (5 mol%)
R
>95% 1a was recovered
4Å MS, DCE, 70 oC, 12 h
. Me
N
Pt(PPh3)2Cl2 (5 mol%)
NTs
>95% 1a was recovered
4Å MS, DCE, 70 oC, 12 h
1a: R = cyclopropyl
c) In situ 1H NMR spectroscopic studies R
R Pt Condition A: [Pt]
To verify the Au- and Pt-catalyzed [3+2] cycloaddition reaction pathways, deuterium labeling experiments were performed as shown in Scheme 5. First, treating 1a with PtCl2 or o [JohnPhosAu]NTf2 at 70 C in the presence of D2O (20.0 equiv), deuterated products [D]-2a and [D]-3a could be formed, suggesting the formation of metallo-carbon inter[11] mediate (Scheme 5, a and b). While conducting the reaco tions at 25 C (room temperature), PtCl2 showed very low catalytic activity (Scheme 5, a). In gold catalysis, 3a was obtained in 40% yield but with no deuterium corporation at 25 o C, indicating that gold complex prefers to coordination with allene moiety instead of C-3 metallation of indole (Scheme 5, b). Then, by using [D]-1a in the presence of Pt and Au catalysts, the corresponding adducts [D]-2a and [D]-3a were obtained in 85% yield with 42% D and 93% yield with 49% D o content at 70 C, respectively (Scheme 5, c). Furthermore, the different reaction results of substrate 1i under Pt or Au catalysis also revealed that there might be two different reaction mechanisms (Table 2, entry 8 vs Table 3, entry 8). Scheme 5. Isotopic Labeling Experiments a)
R
R D
. N
Me NTs
PtCl2 (5 mol%) D2O (20.0 equiv) DCE, 3 h
1a: R = cyclopropyl 70 oC rt
R D
Me NTs +
.
Me NTs [D]-1a 48% yield 43% yield D content: 44% D content: 91% trace, >99% 1a was recovered N
N
[D]-2a
b)
R Me
D [JohnPhosAu]NTf2 (5 mol%)
NTs +
N
D2O (20.0 equiv) DCE, 70 oC, 0.5 h
[D]-1a, 36% yield D content: 68%
[D]-3a, 57% yield D content: 33%
1a
R Me
[JohnPhosAu]NTf2 (5 mol%) D2O (20.0 equiv) DCE, rt, 1 h
N
NTs + 1a, 53% yield
3a, 40% yield c) R D
.
N
PtCl2 (5 mol%) 4Å MS, DCE, 70 oC, 12 h
[D]-2a, 85% yield D content: 42%
Me NTs
[D]-1a, D content: 91%
[JohnPhosAu]NTf2 (5 mol%) 4Å MS, DCE, 70 oC, 6 h
[D]-3a, 93% yield D content: 49%
N
R
Me Me
N
NTs
NTs
. N
.
2a, 81% yield
Not observed Me
R
R
NTs
Au
Condition B: [Au]
1a: R = cyclopropyl
Me
.
N
N
Me NTs
NTs
3a, 90% yield
Not observed Condition A: [Pt] N
N
Ts N
Ph
10 was recovered
Ph
10 was recovered
Pt Not observed
Ph
10
Ts N
Condition C: [Au] N
Ts N
Au Not observed Condition A: PtCl2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 2 h Condition B: [JohnPhosAu]NTf2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 0.5 h Condition C: [JohnPhosAu]NTf2 (1.0 equiv), 4Å MS, d 8-toluene, 70 oC, 2 h
To further verify these cycloaddition reaction mechanisms, several control experiments were also performed and the results are shown in Scheme 6. First, when substrate 1x with a methyl substituent at the C3 position of indole ring was examined under the standard reaction conditions, no desired product was detected in the presence of PtCl2, while cycloadduct 3s was obtained in 70% yield under gold catalysis, which suggested the different catalytic behavior of Pt and Au catalysts (Scheme 6, a). Then, when substrate 1a was examined by employing Pt(COD)Cl2 or Pt(PPh3)2Cl2 as the catalyst, no desired product was obtained, probably due to the steric effect of catalysts (Scheme 6, b). Furthermore, we have also treated substrate 1a and the newly synthesized substrate 10 with stoichiometric PtCl2 or [JohnPhosAu]NTf2 in nuclear magnetic tubes respectively, so as to find direct evidence of the corresponding metallo-carbon intermediates (Scheme 6, c). However, no metallo-carbon intermediate was observed 1 through H NMR spectroscopic analysis in the nuclear mago netic resonance spectrometer at 70 C, presumably due to that the equilibrium largely leans to the starting materials 1a or 10 with metal catalyst and very trace of the metallo-carbon intermediate was formed (see SI-151~SI-154 in the Supporting Information). At the same time, the desired adducts 2a and 3a were obtained in 81% yield and 90% yield, respectively
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when substrate 1a was examined (for more information, see SI-155 in the Supporting Information). Although the full mechanistic details of these transformations remain to be elucidated, plausible mechanisms for the reactions are outlined in Scheme 7 on the basis of the above deuterium labeling and control experiments and pre[2], [3], [4], [11], [12] vious reports to date. For [3+2] annulation, both Pt and gold can form a metallo-carbon intermediate A via reversible C-3 metallation of indole. The following cisaddition to give heterocycle B only takes place when PtCl2 is used presumably due to that gold complexes are sterically hindered. The lack of catalytic activity of Pt(COD)Cl2 and Pt(PPh3)2Cl2 are in accordance with this proposal as well. Then, a Pt-carbene intermediate C is generated, following by 1,2-hydride migration and regeneration of catalyst to yield product 2. As for gold-catalyzed reactions, the coordination of gold complex with allene is a dominant process, though the formation of intermediate A is possible. The intramolecular nucleophilic attack of indole (C3) onto the Au-activated allene A’ forms the alkenylgold(I) complex B’, which diverges into different products. On one hand, similar to Pt catalysis, the desired adducts 3 is formed by tandem cyclization, hydride migration and elimination process through Au-carbene intermediate C’ and alkenylgold(I) complex D’ (path a). The all-carbon quaternary stereocenters in products 2 and 3 were stereoselectively constructed presumably due to the different E and Z configuration of alkenylmetal complexes B and B’. On the other hand, cyclobutane compound 4 is formed via nucleophilic trap of iminum intermediate by C-Au bond 1 (path b). Substrates with cyclopropyl group (R ) tend to give [3+2] cycloadducts 3 probably because the three-membered ring can significantly stabilize the cationic intermediate D’; 2 while substrates with a larger R group disfavored the formation of metal-carbene intermediate C or C’, which led to lower yield of 2 and 3. In addition, the ligands of gold com1 plex as well as the steric and electronic properties of R and 2 R groups make a combined influence on the selective formation of 3 and 4. Scheme 7. Proposed mechanisms for Au- and Pt-catalyzed cycloadditions
CONCLUSION We have disclosed the catalyst-dependent stereodivergent and regioselective synthesis of indole-fused tricyclic system with several contiguous stereocenters through formal cycloadditions of indolyl-allenes in an atom-economical way. The reaction features total reversion of an all-carbon quaternary stereocenter when gold or platinum complex was employed as the catalyst through [3+2] cycloaddition of allene with indole, affording different diazabenzo[a]cyclopenta[cd]azulenes as epimers, respectively. In addition, in the presence of IPrAuCl and AgNTf2, highly regioselective exo-type [2+2] cycloaddition was observed, in which allene moiety acted as a 2C synthon. Different reaction mechanisms have been also proposed on the basis of deuterium labeling experiments. Further investigations on expanding the scope of this reaction towards a variety of novel and potentially useful polycyclic compounds as well as the applications of this protocol to natural product synthesis are in progress.
EXPERIMENTAL SECTION General procedure for the synthesis of product 2: To a flame dried Schlenk tube was added indolyl-allene 1 (0.1 mmol), PtCl2 (0.005 mmol, 5 mol%), 50 mg 4Å MS and the anhydrous solvent DCE (1.0 mL) under argon. Then, the reo sulting solution was allowed to stir at 70 C for 12 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the desired product 2. Compound 2a. A white solid, 86% yield (36 mg). M.p.: 175o 1 178 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.45-0.51 (m, 1H,
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CH2), 0.61-0.67 (m, 1H, CH2), 0.72 (s, 3H, CH3), 0.75-0.88 (m, 2H, CH2), 1.50-1.58 (m, 1H, CH), 2.42 (s, 3H, CH3), 2.46 (dd, J = 11.6 Hz, 11.6 Hz, 1H, CH2), 3.16 (dd, J = 11.6 Hz, 15.6 Hz, 1H, CH2), 3.50 (dd, J = 11.6 Hz, 12.4 Hz, 1H, CH2), 3.61 (dd, J = 4.0 Hz, 12.4 Hz, 1H, CH2), 3.85 (dd, J = 11.6 Hz, 11.6 Hz, 1H, CH2), 4.05 (d, J = 8.8 Hz, 1H, CH), 4.18 (d, J = 8.8 Hz, 1H, CH), 4.25 (dd, J = 4.0 Hz, 15.6 Hz, 1H, CH2), 5.10 (s, 1H, =CH), 6.28 (d, J = 7.6 Hz, 1H, ArH), 6.64 (dd, J = 7.6 Hz, 7.6 Hz, 1H, ArH), 7.08 (dd, J = 7.6 Hz, 7.6 Hz, 1H, ArH), 7.18 (d, J = 7.6 Hz, 1H, ArH), 7.31 (d, J = 8.0 Hz, 2H, ArH), 7.66 (d, J = 8.0 Hz, 2H, 13 ArH). C NMR (CDCl3, 100 MHz, TMS) δ 5.9, 7.9, 11.7, 21.5, 23.6, 46.3, 48.3, 52.6, 54.2, 57.6, 74.7, 105.0, 117.3, 123.8, 126.9, 127.5, 128.0, 129.76, 129.8, 136.4, 143.3, 147.0, 152.2. IR (CH2Cl2) ν 3033, 2922, 2852, 1728, 1601, 1481, 1456, 1378, 1331, 1303, 1281, 1249, 1234, 1184, 1156, 1118, 1091, 1073, 1019, 1003, 974, 924, 906, -1 876, 814, 765, 733, 708, 699, 660 cm . HRMS (ESI) Calcd. for +1 + C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1943.
(m, 2H, CH2), 3.66 (dd, J = 3.2 Hz, 8.4 Hz, 1H, CH), 3.86 (ddd, J = 2.8 Hz, 4.4 Hz, 7.6 Hz, 1H, CH2), 4.23 (d, J = 17.2 Hz, 1H, CH2), 5.14 (d, J = 8.4 Hz, 1H, CH), 6.29 (d, J = 8.0 Hz, 1H, ArH), 6.57 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 6.99-7.04 (m, 2H, ArH), 13 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.72 (d, J = 8.4 Hz, 2H, ArH). C NMR (CDCl3, 75 MHz, TMS) δ 3.1, 6.1, 15.8, 16.6, 21.8, 45.1, 45.7, 52.0, 54.4, 56.6, 64.8, 105.9, 117.2, 124.9, 126.9, 127.4, 128.0, 130.1, 132.5, 135.7, 139.3, 143.8, 151.9. IR (CH2Cl2) ν 3044, 2922, 2842, 1726, 1603, 1486, 1459, 1444, 1376, 1357, 1338, 1267, 1184, -1 1158, 1111, 1090, 1013, 917, 876, 815, 737, 706, 655 cm . HRMS +1 + (ESI) Calcd. for C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1947.
General procedure for the synthesis of products 3, 5 and 6: To a flame dried Schlenk tube was added indolyl-allene 1 (0.1 mmol), [JohnPhosAu]NTf2 (0.005 mmol, 5 mol%), 50 mg 4Å MS and the anhydrous solvent DCE (1.0 mL) under argon. o Then, the resulting solution was allowed to stir at 70 C for 6 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the desired cycloadducts 3, 5 or 6.
Experimental procedures, characterization data, NMR spectra, and crystallographic data (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.
Compound 3a. A white solid, 93% yield (39 mg). M.p.: 130-133 o 1 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.32-0.43 (m, 2H, CH2), 0.65-0.73 (m, 2H, CH2), 1.28-1.36 (m, 4H, CH, CH3), 2.41 (s, 3H, CH3), 2.53 (d, J = 13.2 Hz, 1H, CH2), 2.60 (ddd, J = 2.4 Hz, 12.0 Hz, 14.4 Hz, 1H, CH2), 3.16 (ddd, J = 2.4 Hz, 12.0 Hz, 14.4 Hz, 1H, CH2), 3.54 (d, J = 13.2 Hz, 1H, CH2), 3.75 (dd, J = 14.4 Hz, 14.4 Hz, 1H, CH2), 3.83 (dd, J = 12.0 Hz, 12.0 Hz, 1H, CH2), 3.88 (d, J = 8.4 Hz, 1H, CH), 4.40 (d, J = 8.4 Hz, 1H, CH), 4.84 (s, 1H, =CH), 6.26 (d, J = 8.0 Hz, 1H, ArH), 6.60 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 7.02 (dd, J = 8.0 Hz, 8.0 Hz, 1H, ArH), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.29 (d, J = 8.0 Hz, 2H, ArH), 7.64 (d, 13 J = 8.0 Hz, 2H, ArH). C NMR (CDCl3, 75 MHz, TMS) δ 6.8, 7.4, 9.8, 21.7, 25.2, 50.1, 51.2, 55.0, 55.6, 57.5, 79.8, 105.5, 117.1, 125.0, 126.8, 127.4, 128.0, 129.3, 130.0, 135.3, 143.6, 147.0, 150.5. IR (CH2Cl2) ν 3022, 2919, 2842, 1730, 1601, 1484, 1452, 1369, 1336, 1288, 1272, 1189, 1160, 1129, 1089, 1013, 957, 942, 904, 870, -1 814, 737, 723, 661 cm . HRMS (ESI) Calcd. for +1 + C25H29N2O2S (M+H) Requires 421.1944, Found: 421.1945. General procedure for the synthesis of product 4: A solution of [IPrAuCl] (0.005 mmol, 5 mol %) and AgNTf2 (0.005 mmol, 5 mol %) in DCE (0.5 mL) was stirred at room temperature under argon atmosphere for 15 minutes. To the solution was added a solution of indolyl-allenes 1 (0.1 mmol) in o DCE (0.5 mL), and the reaction mixture was stirred at 70 C for 12 h. The mixture was concentrated in vacuo to yield the crude product, which was purified by flash chromatography on silica gel to furnish the desired adduct 4 as a solid. Compound 4a. A white solid, 26% yield (11 mg). M.p.: 131-134 1 C. H NMR (CDCl3, 400 MHz, TMS) δ 0.19-0.31 (m, 2H, CH2), 0.50-0.65 (m, 2H, CH2), 1.06-1.12 (m, 1H, CH), 1.48 (s, 3H, CH3), 2.38-2.45 (m, 4H, CH, CH3), 2.69 (ddd, J = 3.6 Hz, 7.6 Hz, 11.6 Hz, 1H, CH2), 2.96 (d, J = 17.2 Hz, 1H, CH2), 3.44-3.48 o
ASSOCIATED CONTENT Supporting Information
AUTHOR INFORMATION Corresponding Author [email protected]; [email protected], Fax 86-21-64166128 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for the financial support from the National Basic Research Program of China (973)2015CB856603, Shanghai Municipal Committee of Science and Technology (11JC1402600), and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203 and 20732008).
REFERENCES (1) For selected reviews, see: (a) Sundberg, R. J. Indoles, Academic Press, San Diego 1996. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (d) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9608. (e) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (f) Gazit, A.; Osherov, N.; Posner, I.; Yaish, P.; Poradosu, E.; Gilon, C.; Levitzki, A. J. Med. Chem. 1991, 34, 1896. (g) Pajouhesh, H.; Parsons, R.; Popp, F. D. J. Pharm. Sci. 1983, 72, 318. (h) Finefield, J. M.; Frisvad, J. C.; Sherman, D. H.; Williams, R. M. J. Nat. Prod. 2012, 75, 812. (i) Yang, J.; Wearing, X. Z.; Le Quesne, P. W.; Deschamps, J. R.; Cook, J. M. J. Nat. Prod. 2008, 71, 1431. (j) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666. (k) Duan, S.-W.; Li, Y.; Liu, Y.Y.; Zou, Y.-Q.; Shi, D.-Q.; Xiao, W.-J. Chem. Commun. 2012, 48, 5160. (l) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1998, 63, 4481. (m) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009, 1, 63. (n) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086. (o) Ding, K.; Lu, Y.; NikolovskaColeska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432. (p) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (q) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41,
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7247. (r) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (s) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127. (t) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. (2) (a) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12. (b) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067. (c) Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (d) Ma, S. Chem. Rev. 2005, 105, 2829. (e) Modern Allene Chemistry (Eds.: Krause, N.; Hashmi, A. S. K.), Wiley-VCH, Weinheim, 2004. (f) Bhunia, S.; Liu, R.-S. Pure Appl. Chem. 2012, 84, 1749. (g) Gulías, M.; López, F.; Mascareñas, J. L. Pure Appl. Chem. 2011, 83, 495. (h) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (i) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (j) Lee, J. H.; Toste, F. D. Angew. Chem. Int. Ed. 2007, 46, 912. (k) Lemière, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.; Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (l) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem. Int. Ed. 2007, 46, 909. (m) Trillo, B.; López, F.; Gulías, M.; Castedo, L.; Mascareñas, J. L. Angew. Chem. Int. Ed. 2008, 47, 951. (n) Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6348. (o) Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. Chem. Eur. J. 2009, 15, 3336. (p) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692. (q) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; Fürstner, A. Angew. Chem. Int. Ed. 2010, 49, 2542. (r) Alonso, I.; Faustino, H.; López, F.; Mascareñas, J. Angew. Chem. Int. Ed. 2011, 50, 11496. (s) Rao, W.; Sally; Berry, S. N.; Chan, P. W. H. Chem. Eur. J. 2014, 20, 13174. (t) Hashmi, A. S. K.; Schwarz, L.; Choi, J.; Frost, T. M. Angew. Chem. Int. Ed. 2000, 39, 2285. (u) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2000, 39, 3590. (v) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (w) Suresh, R. R.; Swamy, K. C. K. J. Org. Chem. 2012, 77, 6959. (x) Wang, M.-Z.; Zhou, C.-Y.; Guo, Z.; Wong, E. L.-M.; Wong, M.-K.; Che, C.-M. Chem. Asian J. 2011, 6, 812. (3) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (4) Zhang, G.; Catalano, V. J.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 11358. (5) (a) Luzung, M. R.; Mauleón, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402. (b) Alonso, I.; Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. J. Am. Chem. Soc. 2009, 131, 13020. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783. (6) (a) Huang, L.; Yang, H.-B.; Zhang, D.-H.; Zhang, Z.; Tang, X.-Y.; Xu, Q.; Shi, M. Angew. Chem. Int. Ed. 2013, 52, 6767. (b) Zhang, Z.; Tang, X.; Xu, Q.; Shi, M. Chem. Eur. J. 2013, 19, 10625. (7) For a selection of reviews, see: (a) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96, 635. (c) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813. (d) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev. 2004, 33, 431. (e) Echavarren, A. M.; Mendez, M.; Munoz, M. P.; Nevado, C.; Martin-Matute, B.; Nieto-Ober-huber, C.; Cardenas, D. J. Pure Appl. Chem. 2004, 76, 453. (f) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271. (g) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (h) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (i) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (j) Jiménez-Núñez, E. S.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (k) Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem. Int. Ed. 2008, 47, 4268. (l) Sohel, S. M. A.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269. (m) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (n) Shu, X.-Z.; Shu, D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev. 2012, 41, 7698. (o) Garayalde, D.; Nevado, C. ACS Catal. 2012, 2, 1462. (p) Bongers, N.; Krause, N. Angew. Chem. Int. Ed. 2008, 47, 2178. (q) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (r) Corma, A.; Leyva-Pérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (s) Arcadi, A. Chem. Rev. 2008, 108, 3266. (t) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994. (8) For selected examples of gold or platinum-catalyzed reactions, see: (a) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (b) Watson, D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056. (c) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802. (d) Wang, S.; Zhang, L. J. Am. Chem. Soc.
2006, 128, 14274. (e) Marion, N.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2750. (f) Bolte, B.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010, 132, 7294. (g) Wetzel, A.; Gagosz, F. Angew. Chem. Int. Ed. 2011, 50, 7354. (h) Hashmi, A. S. K.; Yang, W. B.; Yu, Y.; Rominger, F. Chem. Eur. J. 2012, 18, 6576. (i) Hashmi, A. S. K. Wieteck, M.; Braun, I.; Rudolph, M.; Rominger, F. Angew. Chem. Int. Ed. 2012, 51, 10633. (j) Hansmann, M. M.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 2593. (k) Cheong, P. H.; Morganelli, P.; Luzung, M. R.; Houk, K. N.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517. (l) Marion, N.; Lemière, G.; Correa, A.; Costabile, C.; Ramón, R. S.; Moreau, X.; Frémont, P.; Dahmane, R.; Hours, A.; Lesage, D.; Tabet, J.; Goddard, J.; Gandon, V.; Cavallo, L.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem. Eur. J. 2009, 15, 3243. (m) Gawade, S. A.; Bhunia, S.; Liu, R.-S. Angew. Chem. Int. Ed. 2012, 51, 7835. (n) Song, X.-R.; Xia, X.-F.; Song, Q.-B.; Yang, F.; Li, Y.-X.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2012, 14, 3344. (o) Brazeau, J.-F.; Zhang, S. Y.; Colomer, I.; Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 2742. (p) Raducan, M.; Moreno, M.; Boura, C.; Echavarren, A. M. Chem. Commun. 2012, 48, 52. (q) Zheng, H. J.; Huo, X.; Zhao, C. G.; Jing, P.; Yang, J.; Fang, B. W.; She, X. G. Org. Lett. 2011, 13, 6448. (r) Hashmi, A. S. K.; Yang, W. B.; Yu, Y.; Hansmann, M. M.; Rudolph, M.; Rominger, F. Angew. Chem. Int. Ed. 2013, 52, 1329. (s) Hashmi, A. S. K.; Wieteck, M.; Braun, I.; Nosel, P.; Jongbloed, L.; Rudolph, M.; Rominger, F. Adv. Synth. Catal. 2012, 354, 555. (9) The structures of 2a, 3a, 4a and 5-9 have been confirmed by Xray diffraction and their CIF data are shown in the Supporting Information. (10) (a) Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352. (b) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (c) Tarselli, M. A.; Gagné, M. R.; J. Org. Chem. 2008, 73, 2439.
(11) (a) Kaminskaia, N. V.; Ullmann, G. M.; Fulton, D. B.; Kostic, N. M. Inorg. Chem. 2000, 39, 5004. (b) Fürstner, A.; Aïssa, C. J. Am. Chem. Soc. 2006, 128, 6306. (c) Chianese, A. R.; Lee, S. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2007, 46, 4042. (d) Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007, 46, 3410. (e) Sokol, J. G.; Korapala, C. S.; White, P. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2011, 50, 5658. (f) Mullen, C. A.; Campbell, A. N.; Gagné, M. R. Angew. Chem. Int. Ed. 2008, 47, 6011. (g) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208. (h) Mullen, C. A.; Gagné, M. R. J. Am. Chem. Soc. 2007, 129, 11880. (i) Chen, J.-T.; Hsu, R.-H.; Chen, A.-J. J. Am. Chem. Soc. 1998, 120, 3243. (j) Cochrane, N. A.; Nguyen, H.; Gagné, M. R. J. Am. Chem. Soc. 2013, 135, 628. (k) Koh, J. H.; Larsen, A. O.; Gagné, M. R. Org. Lett. 2001, 3, 1233. (l) Kerber, W. D.; Koh, J. H.; Gagné, M. R. Org. Lett. 2004, 6, 3013. (12) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2010, 49, 5232.
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